3-(2&#39;-s-tetrahydropyranyl ethers) of estra-1,3,5(10)-trienes



United States Patent 3,481,924 3-(2-S-TETRAHYDROPYRANYL ETHERS) 0F ESTRA-1,3,5()-TRIENES Pietro de Ruggeri, Carmelo Gandolfi, and Umberto Guzzi, Milan, Italy, assignors to Ormonoterapia Richter S.p.A.,

Milan, Italy, an Italian corporation No Drawing. Filed Dec. 5, 1966, Ser. No. 598,930 Claims priority, application Italy, Oct. 3, 1966, 28,437/66 Int. Cl. C07c 173/00; A61k 17/00 US. Cl. 260-23955 18 Claims ABSTRACT OF THE DISCLOSURE 3-(2' S tetrahydropyranyloxy)-estra-1,3,5(10)-triene fl-anomers are provided in substantially pure form and substantially free from 3 (2'-R-tetrahydropyranyloxy)- estra-1,3,5(l0)-triene ot-anomers. The fi-anomers have prominent lipodiattic activity.

This invention relates to novel compounds of the formula:

wherein R is hydroxy, acyloxy, tetrahydropyranyloxy and wherein the acyl radical in the acyloxy group may be derived from carboxylic acids which are aliphatic, cycloaliphatic, aromatic or araliphatic. Useful aliphatic carboxylic acids include saturated acids having from 1 to 12 carbon atoms. Cyclopentyland cyclohexylpropionic acid are illustrative of the cycloaliphatic acids which may be employed. Benzoic acid or an acyl radical derived from a phenyl, p-amino'phenyl or por o-hydroxyphenyl nucleus may be employed. Phenylacetic, phenylpropionic, phenylcinnamic or phenylpropiolic acids are illustrative of the araliphatic carboxylic acids employed. Dicarboxylic acids such as succinic and glutaric are within the scope of the disclosure.

R is hydrogen, methyl, ethyl, vinyl or ethynyl, or

R and R together are keto-; and

R is 2'-tetrahydropyranyloxy of the formula:

the particular space disposition of the 3,481,924 Patented Dec. 2, 1969 ice bonds around the asymmetric C atom, is such that, the compounds of this invention of the formula:

correspond, as between the two diastereo-isomers, to the diastereo isomer which has the less dextrorotatory optical power and as determined, by means of optical rotatory dispersion (0RD) attributed to it, the absolute 2'-S configuration. Since the hemiacetal bond of the compounds of this invention is similar to the bond of the fl-D-glucopyranoside anomer, the compounds of this invention are here referred to as B- anomers.

As known from organic chemistry, when, a phenol or an alcohol (R-OH) is reacted with dihydropyran to obtain the corresponding tetrahydropyranyl ether, and the starting compound (alcohol or phenol) contains some asymmetric C atoms, the reaction product will be a mixture of two tetrahydropranyl ethers which are not optical antipodes, but diastereo-isomers:

I l l H and the more dextrorotatory anomer (ix-anomer), to which corresponds the absolute 2'-R configuration:

Therefore, the compounds of this invention can be given the following formula:

The mixture of the two diastereo-isomers (that is of diastereoisomers 2'-R and 2-S) is obtained by reacting 3-phenolsteroids with 2,3-dihydropyran in the presence of an acid catalyst.

The fl-anomer compounds, that is the less dextrorotatory ones, as obtained by separating the mixture of the two diastereo-isomers (mixture of a and B anomers), exhibit prominent pharmacological activities, which distinguish them from the more dextrorotatory diastereoisomers (a-anomers) which, on the basis of the preceding convention, will be represented as follows:

For example, in the case of 3-(2'-tetrahydropyranyloxy) estra-1,3,5(10)triene-17 13-01 (estradiol-3-pyranyl), the 18- anomer, i.e. 3 (2'-S-tetrahydropyranyloxy)-estra-1,3,5 (10)-triene-17;8-ol (estradiol-3-pyranyl), that is, of the two diastereo-isomers, the less dextrorotatory form, having a negative Cotton effect, exhibits, when administered by mouth, a complete lack of estrogenic activity, a deficient hypophysis-inhibiting activity, but a prominent lipodiattic activity (decrease of blood cholesterol, modification of the a,B-lipoprotein picture) while the a-anomer that is, of the two diastereo-isomers, the more dextrorotatory form, having a positive Cotton effect in RD, exhibits an opposite picture of moderate estrogenic activity, best anti-ovulatory activity, deficient lipodiattic activity.

This difference in the pharmacological activity can be related to the different space position of the 2'-tetrahydropyranyloxy substituent in relation to the plane of the steroid molecule, and therefore, it may favour or inhibit the linking of the new steroid molecule to the enzymic system which is responsible for the biological activity.

Therefore, the separation of the mixture of the two diastereo-isomers of tetrahydropyranyl ethers of estrogenic steroids into the two components aand p-anomers,

takes a particular significance since only the fl-anomer (i.e. the pure diastereo-isomeric form having a lower dextrorotatory power and a negative Cotton efiect) exhibits a prominent lipodiattic activity.

The preparation can take place by separating the mixture of the uand B-anomers by means of physical methods (fractionated crystallization, gas-chromatography, column chromatography, preparative chromatography on a thin layer) or by starting from the fl-anomer and subjecting the latter to successive reactions.

Thus, for example, by reducing estrone 3-(2'-S-tetrahydropyranyloxy) (that is, of the two diastereo-isomers, the less dextrorotatory form -2'-S-), with NaBH or LiAlH, or with an alcohol and sodium estradiol 3-(2-S- tetrahydropyranyloxy), is obtained. This compound may be oxidized with pyridine-Q0 to obtain estrone-3-(2'-S- tetrahydropyranyloxy) The ethynylation of the latter compound results in the production of 17a-ethynyl-estradiol-3-(2'-Stetrahydropyranyloxy). The 17a-ethynyl substituent of this compound may be totally or partially reduced to produce 17a-ethyl or l7u-vinyl-estradiol-3-(2'-S-tetrahydropyranyloxy).

Thus, estradiol-3-(2'-S-tetrahydropyranyloxy), that is, the less dextrorotatory form of the two diastereo-isomers, having a negative Cotton effect, may be reacted with acid anhydrides or acid chlorides to obtain estradiol-3-(2'-S- tetrahydropyranyloxy)-17fl-acyloxy compounds. However, reaction with 2,3-dihydropyran results in the mixture of .the two 1718-diastereo-isomers of estradiol-bis-[3(2'-S-), 17-(2"-R and S)-tetrahydropyranyloxy], which can be separated to give estra-1,3,5(10)-triene-3-(2-S-tetrahydropyranyloxy)-175(2"-R-tetrahydropyranyloxy) (I) and estra 1,3,5 10)-triene-3 (2'-S-tetrahydropyranyloxy) 17p- (2"-S-tetrahydropyranyloxy) (II):

EXAMPLE 1 3-(2'-S-tetrahydropyranyloxy)-estra- 1,3,5 (10)- triene-17fi-ol 2 parts phosphorus oxychloride is added to a suspension of 100 parts estra-1,3,5(10)-triene-3-ol-17-one in 400 parts 2,3-dihydropyran, under stirring and while cooling the reaction mixture with ice water. After minutes the suspension is warmed gradually to 60 C., while excluding moisture from the reaction vessel, to obtain a complete dissolution of the steroid.

The reaction mixture is cooled to 20 C. and held at this temperature for 20 hours. After neutralization with a solution of sodium methylate in methanol, it is evaporated under vacuum to dryness, the residue is dissolved in 200 parts methanol and 400 parts dioxane, and then parts sodium borohydride is added slowly and with stirring. The resulting mixture is refluxed for 3 hours, concentrated under vacuum to half volume, and diluted with Water.

The precipitate, which is formed, is collected by means of filtration and parts 3-(2-tetrahydropyranyloxy)- estra-l,3,5(lO)-triene-l7/3-ol, a mixture of the two diastereo-isomers (ocand ,B-anomer), is obtained. This product is dissolved in 4000 parts ethyl ether and the solution is successively concentrated to 3500 parts, 2500, 2000 and 1000 parts. The solids, which crystallized every time by spontaneous separation from the mixture, are collected (55 parts) and recrystallized from 2000 parts ethyl ether. Solids precipitating from the solution concentrated to 1500, 1000, 750, 500 ml. are collected and then recrystallized from methanol to give 38 parts pure 3-(2-S-tetrahydropyranyloxy)-estra 1,3,5(l) triene 17p ol, M.P. 154.5-156 c.; [u] =26 (c.=1% in CHCl Cotton effect, negative in ORD.

EXAMPLE 2 3- 2-S-tetrahydropyranyloxy estra-1,3 ,5 (10)-triene 17- one A solution of 20 parts 3-(2'-S-tetrahydropyranyloxy)- estra-l,3,5(l0)-17[3-ol (M.P. 1545-156" 0.; [ct]:26

(CHCl is added to a suspension of 20 parts chromic anhydride in 200 parts pyridine and the resulting solution is held overnight at room temperature. It is diluted with water; the precipitate, which is formed, is filtered out, dried on a water bath and crystallized from ethyl ether to give 16.4 parts 3-(2'-S-tetrahydropyranyloxy)-estra-1,3,5 (10)-triene-l7-one, M.P. 156-158 C.; [a] =+35 (c.=1% in CHCl Cotton efiect, negative in ORD.

EXAMPLE 3 3-(2-S-tetrahydropyranyloxy)-estra-1,3,5( 10) -triene- 17/3-01 EXAMPLE 4 3 parts crude 3-(2-tetrahydropyranyloxy)-estra 1,3,5

17fl-ol-17-acetate 3 parts crude 3-(2-tetrahydropyranylovy)-estra 1,3,5 (10)-triene-l7fi-ol (the mixture of the two disastereoisomers), which is obtained as a by-product in Example 1 (see also US. Patent 3,134,771, May 26, 1964, Examples 8, 9) is dissolved in 8 parts pyridine and combined with 4 parts acetic anhydride. After one night at room temperature, it is diluted with water and the crystallized product is filtered out (3.1 parts). This product 3-(2'-tetrahydropyranyloxy)-estra-1,3,5(10)-triene-17fl-ol 17 acetate (a mixture of the two aand fl-anomers) is dissolved in 8 parts ethyl ether and allowed to be adsorbed on a column of 120 g. activated alumina II according to Beckman. By eluting with petroleum ether-benzene, 1.2 parts of a product is obtained, which, by crystallization from hexane, yields 0.92 part pure 3-(2-S-tetrahydropyranyloxy)-estra-1,3,5(10)-triene-17,8-ol-17-acetate, M.P. 104-105 C.; [0t] =--49 EXAMPLE 5 3- 2'-S-tetrahydropyranyloxy -estra-l ,3,5 )-triene- 1713-01- 1 7-propionate 1.5 parts 3 (2-S tetrahydropyranyloxy) estra 1,3,5 (10)-triene-l7fi-ol is dissolved in 6 parts pyridine and combined with 3 parts propionic anhydride. The reaction mixture is held overnight at room temperature, then diluted with water and filtered. The product, which is collected on the filter, is crystallized from methanol, diluted to give 1.51 parts 3-(2'-S -tetrahydropyranyloxy) -estral,3,5(10)-triene-l7fl-ol-l7-propionate at M.P. 96-97 C.;

[a] =39 (c.=1% in CHCl Cotton effect, negative in 0RD.

EXAMPLE 6 3- 2'-S-tetrahydropyranyloxy) -estral ,3,5( 10)-triene- 1713-01-1 7-valerate Starting with 2 parts 3-(2'-S-tetrahydropyranyloxy)- estra-l,3,5(10)-triene-l7fi-ol and by operating as in the preceding example, but with valeric anhydride, after steam distillation of the reaction mixture, extraction with ether and percolation through an alumina column (hexane as the eluent), there is obtained 1.65 parts 3-(2'-S-tetrahydropyranyloxy)-estra-1,3,5(10)-triene-17B-ol 17 vale'rate, an oily product; [a] =32 (c.=1% in CHCl EXAMPLE 7 3- 2-S-tetrahydropyranyloxy) -e'stral ,3,5 l0 -triene- 175-01- l7-enantate By operating as in the preceding example, but with enantic anhydride, there is obtained 1.72 parts 3-(2'-S- tetrahydropyranyloxy) estra-1,3,5 10)-triene-l7fi-0l 17- enantate, an oily product; [a] =-3l (c.=1% in CHCI EXAMPLE 8 3- 2'-S-tetrahydropyranyloxy) -estra-1 ,3,5 10 -triene- 17 3-01-17-cyclopentylpropionate By operating as in Example 6, but with cyclopentylpropionic acid chloride, there is obtained 1.21 parts 3- (2-S-tetrahydropyranyloxy)-estra-l,3,5 l0) triene 17/3- ol-17-cyclopentylpropionate; [oz] =-25; (c.=1% in CHCl EXAMPLE 9 3-(2'-S-tetrahydropyranyloxy)-l7a-methyl-estra-1,3, 5(10)-triene-17 3-ol To a suspension of 5.4 parts of the sodium derivative of 17a-'methyl-estra-1,3,5(10)-triene-3,17}3-diol in dry benzene, a solution of 2.2 parts D,L-2-chlorotetrahydropyran in 15 parts benzene is added under stirring. This is held under stirring for 4 hours, then filtered and the benzene solution, after repeated washing with alkali and with water to neutrality, is evaporated to dryness to yield a residue of 2.4 parts 3-(2-tetrahydropyranyloxy)-17 xmethylestra-1,3,5(10)-triene-17fl-ol (the mixture of the 2 anomers); [a] =+46; (c.=1% in CHCl By column chromatography through alumina, from the 1:1 and 3:4 petroleum etherzbenzene fractions, 0.35 part pure 3-(2'-S-tetrahydropyranyloxy) 17a methyl-estra- 1,3,5(10) triene 17,3 ol; [u] =37; (c.=1% in CHCl have been isolated. Cotton etfect, negative in 0RD.

EXAMPLE 10 3 (2-S-tetrahydropyranyloxy) estra-1,3,5 10) -triene- 160:,17B-di0l To a solution of 6 parts estra-1,3,5(l0)-triene-3,16a, 17,8-triol in 25 parts dry dimethylformamide and 25 parts benzene, 10 parts finely powdered silver carbonate and successively, under stirring, 2.5 parts d,1,2-chlorotetrahydropyran are added. The mixture is held under stirring and in the dark for 15 hours, then filtered, and, after dilution with parts benzene, extracted repeatedly with alkali and washed with water. Then, it is dried over sodium sulfate, evaporated to dryness to obtain 1.8 parts 3 (2-tetrahydropyranyloxy)-estra-1,3,5(IO-triene- 1601,17B-di0l; [a] ='+55; (c.=1% in CHCl a mixture of the two anomers. The mixture is crystallized from ethyl ether and the precipitated solid is discarded. The dried mother liquors (0.9 part) are chromatographed through alumina (benzene-ethyl ether as the eluent) and from the 9:1 and 7:3 fractions, by repeated crystallizations from acetone-ether, there is obtained 0.18 part 3- (2'-S-tetrahydropyranyloxy) estra-1,3,5 l0)-triene-l6a, 17,8-diol; [a] =29; (c.=1% in CHCl 7 EXAMPLE 11 3-(2-S-tetrahydropyranyloxy)-17a-ethynyl-estra-1,3 5( 10) -triene-1 7 3-01 A solution of 1.5 parts 3-(2'-S-tetrahydropyranyloxy)- estra-1,3,5(10)-triene-17-one in a mixture of 14 parts toluene and 120 parts dry ethyl ether, is deaerated by passing a nitrogen current through it for 20 minutes at the temperature of C.

The solution is then saturated with acetylene, and then 23 parts of a 13% potassium tert-butylate solution in butanol is added, during 15 minutes, the acetylene current through the mixture being maintained for 8 hours; and the mixture is thereafter stored for days at --5 C.

The formed precipitate is collected by filtration, washed on the filter with 10 parts dry ether, dried under vacuum, treated with a 12% NH Cl solution in water.

The separated product is collected by filtration, washed with water to neutrality and then recrystallized from diluted methanol 1.25 parts 3-(2'-S-tetrahydropyranyloxy)-17a-ethynyl-estra-l,3,5 (10)-t1'i6I1B-17a-01, having a MP. of 99-101 C. and [u] =78; (c.=1% in CHCl is obtained.

EXAMPLE 12 3-(Z'S-tetrahydropyranyloxy) -l7a-vinyl-estra-l,3, 5(10)-triene-17fi-ol 1.2 parts 3-(2'-S-tetrahydropyranyloxy)-l7a-ethynylestra-1,3,5(10)-triene-17fi-ol (see Example 11) is dissolved in 8.5 parts pyridine and 7.5 parts dioxane. There is added 0.65 part Pd 2% on calcium carbonate, and hydrogen is passed up to the absorption of one molar equivalent of H The catalyst is then filtered OK, the solution evaporated to dryness and by crystallization from aqueous methanol, 0.96 part 3-(2'-S-tetrahydropyranyloxy)-17a-vinyl-estra 1,3,5(10) triene 175-01; [a] =-37; (c.'=1'% in CHCl is obtained.

EXAMPLE 13 3 (2'-S-tetrahydropyranyloxy) -17a-ethyl-estra-l,3 5 10) -triene-17;3-ol

2 parts 3-(2-S-tetrahydropyranyloxy) 170: ethynylestra-1,3,5(10)-triene-17fl-ol is dissolved in 25 parts 95% ethanol and hydrogenated in the presence of 1 part Pd 5% on calcium carbonate. The catalyst is filtered off, the filtrate is concentrated to a small volume, and diluted with water. There is obtained 1.82 parts 3-(2'-S-tetrahydropyranyloxy)-17u-ethyl-estra 1,3,5 10)-triene-17fi-ol; [u] '=33; (c.=1% in CHCl Cotton efiect, negative in 0RD.

EXAMPLE 14 17a-methyl-estra-1,3,5( 10)-triene-bis-[3-(2-S) ,17fl (2") -tetrahydropyranyloxy] A solution of 0.06 part p-toluenesulfonic acid in benzene is added to a solution of 2.6 parts 3-(2'-S-tetrahydropyranyloxy) -17a-methyl estra-1,3,5 10 -triene-175- 01 (see Example 9) containing 0.9 part 2,3-dihydropyran.

The mixture is maintained for 12 hours at room temperature, then it is neutralized with a sodium methylate solution, washed with water to neutrality and evaporated to dryness.

By crystallization from ethyl ether-methanol, there is obtained 2.2 parts 17u-methyl-estra-1,3,5(10)-triene-bis- [3-(2'-S), 175(2")-tetrahydropyranyl ether]; M.P. 101- 104 C.; [a] =38 C. (c.=1% in CHCl EXAMPLE 15 17a-ethynyl-estra-1,3,5 (10)-triene-bis-[3-(2'-S) 1713(2") -tetrahydropyranyloxy] By operating at 0 C., 2 parts 3-(2-S-tetrahydropyranyloxy) 17a ethynyl-estra-1,3,5(10)-triene-17fi-ol 8 are dissolved in 10 parts 2,3-dihydropyran and combined with 0.025 part POCl After 12 hours at 2-5 C., the mixture is diluted with 200 parts ethyl ether, and the organic phase is washed with a 5% NaHCO solution and with water.

Then, it is evaporated to dryness and crystallized from ethyl ether to obtain 1.73 parts 170: ethynylestra- 1,3,5(l0) triene bis-[3(2'-S)-17fi(2")-tetrahydropyranyloxy]; M.P. -146 0.; [a] =-46 (c.=l% in CHCl EXAMPLE l6 Estra-1,3,5 10)-triene-bis-[3 (2'-S)-17p(2")- tetrahydropyranyloxy] A solution of 0.01 part p-toluenesulfonic acid in 5 parts benzene and 0.4 part 2,3-dihydropyran are added to a solution of 1 part 3-(2'-S-tetrahydropyranyloxy)-estra- 1,3,5(l0)-triene l7fi-ol in 10 parts benzene, while cooling to +5 C. The mixture is held at 5 C. for 6 hours, neutralized with sodium methylate, washed with water to neutrality, and evaporated to dryness, to obtain, after percolation through an alumina column, 0.66 part of a waxy compound which is estra-1,3,5(10)-triene-bis- [3-(2-S), 175(2")-tetrahydropyranyloxy]; [a] =-32 (c;=1% in CHCl We claim:

1. 3 (2' S tetrahydropyranyloxy)-estra-l,3,5(10)- triene p-anomer substituted at the 17 carbon atom by the grouping wherein R is hydroxy, acyloxy or tetrahydropyranyloxy and R is hydrogen, methyl, ethyl, vinyl or ethynyl or R and R together are keto, the acyl radical of said acyloxy group being derived from a saturated aliphatic carboxylic acid of 1 to 8 carbon atoms, cyclopentylpropionic acid, cyclohexylpropionic acid, benzoic acid, phenylacetic acid, phenylpropionic acid, phenylcinnamic acid or phenylpropiolic acid, said fl-anomer being in substantially pure form and being substantially free from the corresponding 3 (2'-R-tetrahydropyranyloxy) -estra- 1,3,5(10)-triene a-anomer.

2. The compound of claim 1 wherein the p-anomer is 3 (2'S-tetrahydrOpyranyloxy) estra l,3,5(l0)-triene- 1713-01.

3. The compound of claim 1 wherein the fi-anomer is 3 (Z'S-tetrahydropyranyloxy) estra l,3,5(10)-triene- 17-one.

4. The compound of claim 1 wherein the fl-anomer is 3 (ZS-tetrahydropyranyloxy) estra 1,3,5 (10)-triene- 17fl-o1-17-acetate.

5. The compound of claim 1 wherein the fl-anomer is 3 (ZS-tetrahydropyranyloxy) estra 1,3,5(10)-triene- 17fi-ol-17-propionate.

6. The compound of claim 1 wherein the p-anomer is 3 (ZS-tetrahydropyrauyloxy) estra 1,3,5(10)-trienel7 6-ol-17-valerate.

7. The compound of claim 1 wherein the fi-anomer is 3 (Z'S-tetrahydropyranyloxy) estra 1,3,5(10)-tn'ene- 17,8-ol-17-enantate.

8. The compound of claim 1 wherein the p-anomer is 3 (Z'S-tetrahydropyranyloxy) estra 1,3,5(l0)-triene- 175-01-17-cyclopentylpropionate.

9. The compound of claim 1 wherein the fi-anomer is 3 (Z'S-tetrahydropyranyloxy) estra l,3,5(10)-trienel7fl-ol-l7-benzoate.

10. The compound of claim 1 wherein the p-anomer is 3 (Z'S-tetrahydropyranyloxy) estra 1,3,S(10)-tn'ene- 1713-01-l7-phenylpropionate.

11. The compound of claim 1 wherein the fl-anomer is 3 (2S-tetrahydropyranyloxy) methyl estral,3,5(10)-triene-17B-ol.

12. The compound of claim 1 wherein the fi-anomer is 3 (ZS tetrahydropyranyloxy) estra 1,3,5(10)- triene-16a,17fi-diol.

13. The compound of claim 1 wherein the B-anomer is 3 (2'S tetrahydropyranyloxy) 17a ethynyl estra- 1,3,5(10)-triene-17B-ol.

14. The compound of claim 1 wherein the fl-anomer is 3 (2'S tetrahydropyranyloxy) 17oz vinyl estra- 1,3,5(10)-triene-17/3-ol.

15. The compound of claim 1 wherein the fi-anomer is 3 (Z'S-tetrahydropyranyloxy) 17m ethyl estra- 1,3,5 l 0) -triene-17,B-ol.

16. The compound of claim 1 wherein the B-anomer is 17m methyl estra 1,3,5(10) triene bis-[3-(2'-S), 17;3(2) -tetrahydropyranyloxy] 17. The compound of claim 1 wherein the fi-anomer is 170: ethynyl estra 1,3,5(10) triene bis-[3-(2-S), 17B- (2")-tetrahydropyrany1oxy] 18. The compound of claim 1 wherein the fi-anomer UNITED STATES PATENTS 2/1959 Hogg et a1. 260397.45 5/1964 de Ruggieri et a1. 260239.55

OTHER REFERENCES Gandolfi et 21., Gazz. Chim. Ital. 94, June 1964, pp.

10 67594, 681 and 690', relied upon.

Gardi et al., Gazz. Chim. Ital. 93, August 1963, pp. 1028-1043, 1035 relief upon.

de Ruggieri et al., J.A.C.S. 81, November 1959', pp.

15 57255727, 5725, relied upon.

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R' 260999 

